The lungs in the chest, as well as abdominal organs such as the stomach, the intestines, the liver, and the heart are each wrapped in membranes such as pleura, peritoneum, and pericardium. A portion that covers the surface of such a membrane is referred to as mesothelium. A tumor that is developed from such mesothelium is referred to as a mesothelioma. Mesotheliomas are classified into pleuramesothelioma, peritoneal mesothelioma, pericardial mesothelioma, and the like depending on the primary sites.
Mesotheliomas are also classified into malignant mesothelioma and benign mesothelioma. Malignant mesothelioma is further classified into localized mesothelioma and diffuse mesothelioma. The relationship of pleuramesothelioma and peritoneal mesothelioma with asbestos exposure has been proved. In recent years, mesothelioma has been on the increase.
Conventional treatments for malignant mesothelioma are mainly trimodality treatments using surgical therapy, chemotherapy, and radiotherapy in combination. The 5-year survival rate is still 10% or less, and malignant mesothelioma is an intractable solid cancer.
Surgical therapy includes pleurectomy, pleurolysis, and extrapleural pneumonectomy. However, the former therapy is problematic in terms of curability and the latter therapy is problematic because of its many complications. A variety of chemotherapy regimes have been attempted, including a combination of pemetrexed+CDDP, but they are not always drastically effective and often cause adverse reactions. Radiation therapy merely plays an ancillary role. In recent years, systemic medication with IL-2, IFN-γ, or the like has been attempted as cytokine therapy. However, cytokine therapy causes strong adverse reactions and cytoreductive effects are not obtained to the extent expected. Hence, definite effects cannot be expected from any therapy. The creation of a stronger treatment strategy for malignant mesothelioma is a pressing need.
REIC/Dkk-3 has been identified at Okayama University as a gene whose expression is lowered in association with immortalization of normal human fibroblasts. It was clarified later that REIC/Dkk-3 is homologous to a mammalian gene member of the Dkk (dickkopf) gene family involved in formation of a Xenopus head (see International Patent Publication WO01/038523 Pamphlet and Tsuji, T. et al., BiochemBiophys Res Commun 268, 20-4 (2000)). It has been revealed by examination using a human prostatic cancer-derived cell line that infection with the REIC/Dkk-3 adenovirus (hereinafter, Ad-REIC) results in generation of intracellular stresses, activating c-jun N-terminal Kinase (JNK) and thus inducing apoptosis (see Abarzua et al., Cancer Res. 65, 9617-9255 (2005)).